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“Born to be bad” — some cancers spread before detection

Many metastatic colorectal cancers appear "born to be bad," spreading to other organs before any diagnosis has been made, say Stanford researchers.

Colorectal cancer is the second leading cause of death from cancer in the United States. As with most cancers, it's long been thought that early detection through routine screening is the key to stopping the spread of the disease to the liver or the brain (its preferred sites of metastasis).

Now, cancer geneticist Christina Curtis, PhD, together with postdoctoral scholar Zheng Hu, PhD, have learned that nearly 80 percent of metastatic colorectal cancers have likely already metastasized before the primary tumor is clinically detectable. They published their results in Nature Genetics.

The finding turns a common belief about cancer development on its head.

As I describe in our release:

Researchers and clinicians have assumed that cancers acquire the ability to metastasize through the gradual accumulation of molecular changes over time. These changes, the thinking goes, confer specific traits that eventually allow cancer cells to escape the surrounding tissue, enter the bloodstream and take up residence in new locations. In this scenario, metastasis, if it occurs, would be a relatively late event in the evolution of the primary cancer.

Curtis and Hu were particularly interested in figuring out when and how the original, or primary, colorectal tumors acquired the ability to metastasize. To do so, they had to study both types of tumors from a series of individual patients, comparing the genomes of the cancer cells and then developing an new computational framework to piece the information together.

From our release:

Studying tumor biopsies, the researchers compared patterns of genetic mutations in the primary tumors of 23 patients with the patterns in their liver or brain metastases. They looked for similarities or differences between primary and metastatic cancers obtained from the same person. They then used those patterns to create a kind of evolutionary tree of each patient's cancer -- similar to one a biologist might make to trace the evolution of an animal species from a single ancestor.

Their results weren't exactly what they had suspected.

As Curtis explained:

This finding was quite surprising. [...] The cells that formed the metastasis were more closely related to the ancestors of the primary tumor than its present-day relatives. Moreover, the metastasis shared early drivers present in the 'trunk' of the evolutionary tree, but harbored few additional drivers. This suggested that these cancers acquired metastatic competence very early on during their growth.

The researchers went on to identify specific combinations of mutations that occur more frequently in metastatic disease.

Curtis emphasizes that not all colorectal cancers metastasize (they specifically studied a subset of patients with metastatic cancer). She also cautioned against feeling like early detection is unimportant. On the contrary, it's even more urgent.

"These data indicate that metastasis can occur early in human colorectal cancer and highlights the critical need for the earlier detection of aggressive disease," Curtis said. "New biomarkers based on specific combinations of alterations might enable the identification of potentially lethal colorectal tumors at an earlier stage so that they may be intercepted and appropriately treated, potentially with therapies directed against their specific aberrations."

Image by geralt

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